Hormone Dependent Cancer

Regulation of chromatin through DNA methylation and histone modification is a dynamic process by which cells modulate gene expression whilst retaining nucleotide stability. In cancer, many of these pathways become aberrant, resulting in genome instability and uncontrolled gene expression. Therefore, understanding the biochemical processes involved in chromatin regulation is paramount in developing new treatments in cancer chemotherapy.

Lysine-specific demethylase 1 (LSD1) selectively relieves histone marks through demethylation and can act as a coactivator or corepressor of gene expression, depending on its histone target. The purpose of this research is to understand the interplay between LSD1 and epigenetic regulation and identify which components are attractive drug targets. Specifically, this examines:

• The role of posttranslational modifications in recruiting LSD1 to chromatin and other protein complexes in cancer.
• The extent to which the catalytic activity of LSD1 is required for stemness, cellular maintenance and development.  

To address these areas, we utilize state-of-the-art molecular, cellular and biochemical techniques in combination with next generation technologies such as ChIP-seq, RNA-seq and mass-spectrometry. In parallel, we have developed a number of gain and loss-of-function models in transgenic, knockout (KO) or knockin (KI) mice with which we can regulate the expression and activity of LSD1 under the control of Cre recombinase, providing a powerful tool in examining the dynamic response of LSD1 in vivo.

Literature

Metzger E., Stepputtis S.S., Strietz J., Preca B.T., Urban S., Willmann D., Allen A., Zenk F., Iovino N., Bronsert P., Proske A., Follo M., Boerries M., Stickeler E., Xu J., Wallace M.B., Stafford J.A., Kanouni T., Maurer J., Schüle R. (2017. KDM4 Inhibition Targets Breast Cancer Stem-like Cells. Cancer Res. 77(21):5900-5912. doi: 10.1158/0008-5472